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Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Zhou, Bing; Hu, Jiantao; Xu, Fuming; Chen, Zhuo; Bai, Longchuan; Fernandez-Salas, Ester; Lin, Mei; Liu, Liu; Yang, Chao-Yie; Zhao, Yujun; McEachern, Donna; Przybranowski, Sally; Wen, Bo; Sun, Duxin; Wang, Shaomeng.
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  • Zhou B; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Hu J; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Xu F; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Chen Z; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Bai L; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Fernandez-Salas E; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Lin M; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Liu L; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Yang CY; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Zhao Y; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • McEachern D; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Przybranowski S; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Wen B; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Sun D; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • Wang S; University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
J Med Chem ; 61(2): 462-481, 2018 01 25.
Article en En | MEDLINE | ID: mdl-28339196
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Factores de Transcripción / Proteínas Nucleares / Indoles / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Factores de Transcripción / Proteínas Nucleares / Indoles / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos